Project Summary Parkinson?s disease (PD) is a devastating neurological disorder, afflicting over 50 million people worldwide with bradykinesia, tremor, and rigidity. PD is characterized by dopamine depletion (DD) in the basal ganglia, which leads directly to motor symptoms, changes in basal ganglia neural circuits, and increased ? oscillations (13-30 Hz) in many nuclei. However, the mechanisms by which these neural circuit changes, activity patterns, and motor deficits are generated and the connections between them remain poorly understood. One major circuit rewiring in DD occurs in the striatum, where fast spiking interneurons (FSIs) selectively double their connection probability to D2-receptor-expressing medium spiny neurons (MSNs). These MSNs project to the globus pallidus externa (GPe) whose neurons send feedback projections to FSIs, closing the pallidostriatal loop. This pallidostriatal feedback projection has been well-characterized anatomically and more recently, computationally, but its role in disease states has been understudied In our recently published computational model, I demonstrated that DD-induced increases in striatal connectivity are sufficient to generate and amplify ? oscillations throughout the circuit through a mechanism which requires the pallidostriatal feedback projection. This novel model of ? oscillation amplification has major implications in understanding Parkinson?s disease pathology. The goal of this study is to investigate how the pallidostriatal circuit functions in DD and interacts with other chronically oscillating basal ganglia nuclei through theoretical and in vivo investigations. In Aim 1, we will investigate how disrupting the pallidostriatal circuit in a mouse model of Parkinson?s disease affects oscillatory dynamics in the GPe. This will test whether the pallidostriatal circuit?s propensity to resonate at ? frequencies has a generating, amplifying, or destructive effect on pathological oscillations in DD. In Aim 2, we employ a two-pronged computational and experimental approach to investigate how the pallidostriatal circuit interacts with oscillations generated by the GPe?s recurrent connections with the subthalamic nucleus (STN). Through in vivo manipulations of the pallidostriatal circuit while recording from the STN, we will determine whether the pallidostriatal circuit?s effects on oscillations can be transferred to other basal ganglia nuclei and if the oscillations which interact with pallidostriatal ? synchrony are derived from the STN-GPe loop or elsewhere. Pairing this with an extension of our computational model will provide details about variables impossible to measure experimentally and give insights into the underlying mechanisms by which these circuits interact. A thorough understanding of the pallidostriatal circuit?s role in causing pathological oscillatory synchrony in PD will provide a better understanding of basal ganglia function and dysfunction in disease, and may illuminate new targets and interventions to help treat PD in human patients.